Current therapy of the ichthyoses, including the lipid synthetic, autosomal recessive congenital ichthyoses (ARCI), is largely symptomatic, and often irrational; e.g., when removal of excess scale interferes with homeostatic responses that allow patients to survive in a harsh, terrestrial environment. At the other extreme, corrective gene therapy, though seductive in concept, remains a distant dream, with many potential pitfalls. Our proposed new approach has been first, to identify pathogenic mechanisms in ARCI patients, using biopsies from patients and animal models, as well as organotypic models (HEEs) of the ARCI, prepared from either patient fibroblast or keratinocyte cell lines, or from normal fibroblasts by CRISPR/Cas 9 technology. Using ultrastructural, lipid biochemical, and RNA-seq technology, we will assess both the cellular and genetic basis for these disorders, and identify compensatory mechanisms that account for patient survival. We then will assess whether this new information can translate into readily-deployable, topical therapies for patients after their initial optimization in ARCI HEEs, and in disease-appropriate animal models. Following identification and optimization of effective therapy in the animal models, we will initiate clinical studies for these patients, supported by a parallel grant proposal. If successful, this approach should initiate a paradigm shift in how many of the ichthyoses will be treated in the future. Finally, since the cutaneous phenotype reflects pathogenic mechanisms that also are on-going in syndromic disorders with extracutaneous disease manifestations, successful pathogenesis-based therapy for these ARCI could also identify comparable approaches to treat/prevent the extracutaneous manifestations of these disorders.